Predictive Biomarkers in Oncology

Question 1

What do biomarkers in oncology assess and treat?

Answer 1

Assess the likelihood that the tumour will respond to a particular drug

Treat each cancer as a reflection of its molecular profile and not as a set of tissue-specific diseases with generic treatments

Question 2

What is and can be measured in oncology?

Answer 2

Is: Blood - ctDNA
Tumour – somatic changes, gene & protein expression

Can: CTC, exosomes, Immune profile, metabolites

Oral (swab) – microbiome, volatiles
TME cell types

Question 3

What is ER (oestrogen receptor) positive breast cancer treated with?

What is a challenge relating to this?

Answer 3

Anti-oestrogen/aromatase inhibitors

Mutations can confer desensitisation to anti hormonal actions typically generating oestrogen receptor that no longer requires ligand to downstream effects

Question 4

1. What is considered the first designer targeted therapy?
2. What does this involve?
3. What is an issue relating to this?

Answer 4

Chronic myelogenous leukemia(CML) treatment

Philadelphia chromosome – translocation between chromosome 9 and 22 is highly enetrant in CML. Leads to generation of BCR-ABL, this fusion protein has high tyrosine kinase activity.

Imatinib: Tyrosine Kinase Inhibitor, used as therapeutic

3. Resistance to imatinib occurs in about 10–15% of patients

30–50% of patients with secondary resistance to imatinib have a catalytic domain mutation

dasatinib and nilotinib can be deployed 2nd line

The level of resistance to imatinib, nilotinib and dasatinib depends on the mutation identified

Question 5

What did Soverini, et al. 2011 find?

Answer 5

G250E and E255K lead to profound change in sensitivity to Imatinib

However modest sensitivity change to Dasatinib drug - can be used as a second line therapeutic

Question 6

Why is EGFR an ‘attractive’ target?

Answer 6

Druggable growth factor receptor with tyrosine kinase activity

Expression known to be upregulated in some cancers

Associated with poor outcomes in some cancers

Experimentally associated with transformation (erythroblastosis virus)

Question 7

What is one confounding variable of anti–EGFR therapies such as Iressa?

Answer 7

20-30% of Non-small-cell lung carcinoma
(NSCLC) have mutant K-Ras

K- ras is downstream of EGFR

Activated KRAS mutations are strongly
associated with resistance to anti–EGFR therapies (loss of drug binding).

Question 8

If KRAS is not mutated, EGFR may be mutated.

What can overcome this?

Answer 8

3rd generation covalent inhibitors can overcome

the frequent resistance mutation T790M

Question 9

Discovery science and validation drive predictive biomarker.

What is an example

Answer 9

BRCA1 and BRCA2 encode proteins that are components of the homologous recombination (HR) DNA-repair pathway

poly-ADP(ribose) polymerase (PARP) is a DNA-damage- sensing nuclear enzyme involved in DNA repair

breast cancer cells defective in BRCA1 or BRCA2 are highly sensitive to PARP inhibition

inhibitors of PARP in BRCA1/2 deficient tumours

BRCA1 or 2 deficiency prescribes PARP inhibitor use

Question 10

What mutations are found in Non-small-cell lung carcinoma (NSCLC)?

What treatment is available for this?

Answer 10

ALK

Chromosomal inversion leading to ALK fusion reported 2007

Crizotinib an Alk inhibitor approved in 2011
Four 2nd generation inhibitors now on the market (2020)

Question 11

How is ALK rearrangement measured?

Answer 11

Break Apart FISHProbe Kit is a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens to aid in identifying those patients eligible for treatment with Crizotinib or other inhibitors

Question 12

What did Pailler et al. 2019 find?

Answer 12

Acquired Resistance Mutations to ALK Inhibitors in Non-small-cell lung carcinoma (NSCLC)

Question 13

What information is being employed?

Answer 13

Evidence of a therapeutic target’s role

Evidence of target integrity

Precise nature of any altered target

Evidence of confounding events

Evolution of the tumour on progression

Question 14

V211D mutation in MEK1 causes resistance to MEK inhibitors in colon cancer.

1. How was this found?
2. What can be concluded from this?

Answer 14

1. MAP2K1 V211D mutant found to be insensitive to inhibition when both drugs introduced – Binimetinib and Cobimentib (allosteric inhibitors of MEK1)

2.

• Demonstration of resistance
• Correlation with progressive disease
• Demonstration that mutant variant sensitive to a distinct class of inhibitors - MAP2K1 V211D was sensitive to MAP855 (catalytic site inhibitor)

Effectively define a predictive biomarker relevant to MEK-dependent recurrence

Question 15

Strong drivers of Predictive Biomarkers in Oncology are associated with?

Answer 15

Toxicity
Cost
Treatment opportunity
Speed of development

Question 16

What are challenges associated with

Predictive Biomarkers in Oncology are associated with?

Answer 16

Sampling (changing landscape)
Strength of association (life threatening condition)
Additional cost

Question 17

Nilotinib, an analogue of imatinib, has not demonstrated activity in a similar patient population.

Answer 17

False

Nilotinib, an analogue of imatinib, has demonstrated activity in a similar patient population.

Question 18

Dasatinib, a dual Bcr-Abl/Src kinase inhibitor, has shown efficacy against all imatinib-resistant Bcr-Abl mutations except for T315I.

True or false

Answer 18

True